A Novel CpG Methylation Risk Indicator for Predicting Prognosis in Bladder Cancer.
A Novel CpG Methylation Risk Indicator for Predicting Prognosis in Bladder Cancer.
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DOI：
10.3389/fcell.2021.642650
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发表时间：
2021
影响因子：
5.5
通讯作者：
Song D
中科院分区：
文献类型：
--
作者：
Guo Y;Yin J;Dai Y;Guan Y;Chen P;Chen Y;Huang C;Lu YJ;Zhang L;Song D
膀胱癌（BLCA）是世界上最常见的癌症之一。在很大一部分BLCA患者中，切除后疾病复发和/或进展，这仍然是BLCA治疗中的一个主要临床问题。因此，确定治疗分层的预后生物标志物至关重要。我们研究了CpG甲基化作为BLCA患者预后生物标志物的可能性。总体而言，来自癌症基因组图谱（TCGA）的357名BLCA患者被随机分为训练和内部验证队列。采用最小绝对收缩和选择操作（LASSO）和支持向量机-递归特征消除（SVM-RFE）筛选候选CpG，构建甲基化风险评分模型，并通过Kaplan-Meier分析验证其在验证队列中的预后价值。生成风险曲线以揭示整个随访期间的风险节点。基因集富集分析（GSEA）用于揭示与甲基化模型相关的潜在生物学途径。进行定量实时聚合酶链反应（PCR）和蛋白质印迹以验证甲基化基因的表达水平。在合并通过两种算法获得的CpG后，对应于TNFAIP 8L 3、KRTDAP、APC、ZC 3 H3、COL 9A 2、SLCO 4A 1、POU 3F 3和ADARB 2的8个基因的CpG甲基化是建立BLCA（MRSB）甲基化风险评分的主要候选预测因子，该评分用于将患者分为高风险和低风险进展组（p < 0.001）。MRSB的有效性在内部队列中得到验证（p < 0.001）。在MRSB高危组中，风险曲线在治疗后10个月内显示出一个宽的高峰，而在2年左右观察到一些平缓的峰。此外，包括MRSB，年龄，性别和肿瘤临床分期的诺模图被开发用于预测个体进展风险，并且其表现良好。生存分析显示MRSB的有效性，在基于临床特征的所有亚组分析中仍然具有显著性。MRSB和相应基因的功能分析揭示了影响肿瘤进展的潜在途径。实时定量PCR和蛋白质印迹的验证显示TNFAIP 8L 3在BLCA组织中上调。我们开发了MRSB，这是一种基于八个基因的甲基化特征，具有很大的潜力用于预测BLCA的手术后进展风险。
Bladder cancer (BLCA) is one of the most common cancers worldwide. In a large proportion of BLCA patients, disease recurs and/or progress after resection, which remains a major clinical issue in BLCA management. Therefore, it is vital to identify prognostic biomarkers for treatment stratification. We investigated the efficiency of CpG methylation for the potential to be a prognostic biomarker for patients with BLCA. Overall, 357 BLCA patients from The Cancer Genome Atlas (TCGA) were randomly separated into the training and internal validation cohorts. Least absolute shrinkage and selector operation (LASSO) and support vector machine-recursive feature elimination (SVM-RFE) were used to select candidate CpGs and build the methylation risk score model, which was validated for its prognostic value in the validation cohort by Kaplan–Meier analysis. Hazard curves were generated to reveal the risk nodes throughout the follow-up. Gene Set Enrichment Analysis (GSEA) was used to reveal the potential biological pathways associated with the methylation model. Quantitative real-time polymerase chain reaction (PCR) and western blotting were performed to verify the expression level of the methylated genes. After incorporating the CpGs obtained by the two algorithms, CpG methylation of eight genes corresponding to TNFAIP8L3, KRTDAP, APC, ZC3H3, COL9A2, SLCO4A1, POU3F3, and ADARB2 were prominent candidate predictors in establishing a methylation risk score for BLCA (MRSB), which was used to divide the patients into high- and low-risk progression groups (p < 0.001). The effectiveness of the MRSB was validated in the internal cohort (p < 0.001). In the MRSB high-risk group, the hazard curve exhibited an initial wide, high peak within 10 months after treatment, whereas some gentle peaks around 2 years were noted. Furthermore, a nomogram comprising MRSB, age, sex, and tumor clinical stage was developed to predict the individual progression risk, and it performed well. Survival analysis implicated the effectiveness of MRSB, which remains significant in all the subgroup analysis based on the clinical features. A functional analysis of MRSB and the corresponding genes revealed potential pathways affecting tumor progression. Validation of quantitative real-time PCR and western blotting revealed that TNFAIP8L3 was upregulated in the BLCA tissues. We developed the MRSB, an eight-gene-based methylation signature, which has great potential to be used to predict the post-surgery progression risk of BLCA.
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14.9
作者：
Ritchie ME;Phipson B;Wu D;Hu Y;Law CW;Shi W;Smyth GK
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作者：
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通讯作者：
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